Hematopoietic Stem-Cell Transplant

In early 1993, researchers began to investigate the role of hematopoietic stem cell transplantation (HSCT) for multiple sclerosis (MS). This form of treatment-which is also being studied in breast cancer-consists of very high dose chemotherapy that destroys not only the immune compartment of blood cells thought to be involved in MS but healthy blood cells as well. This treatment then infuses new "seed" stem (hematopoietic) cells into a person's body, which will mature into blood cells and reconstitute the blood. Although the rationale for this form of therapy in MS makes sense, studies conducted since 1993 have been disappointing.

During the recent ACTRIMS meeting, experts in MS debated the pros and cons of HSCT and whether studies with this form of therapy should be pursued.

"Although we have heard an exquisite rationale for HSCT therapy as a treatment for MS, there are many challenges to be overcome before we decide whether we should move on with this therapy," stated Jerry Wolinsky, MD, University of Texas, Houston.

Preliminary results of Phase I studies of HSCT in MS patients have been disappointing. The mortality rate with this procedure is approximately eight percent-a rate that is unacceptably high. In addition, rates of disease progression are between 20 percent and 25 percent following HSCT-a rate similar to the natural history of the disease in patients who do not receive treatment for MS. Thus far, the evidence argues against treating those with primary progressive MS (PPMS) and those with an Expanded Disability Status Scale (EDSS) of 6.5. If HSCT is studied in patients with early-stage MS, it will take at least five more years to know if treatment in this group makes a difference. Further, this would be a difficult study to conduct with such a high mortality rate, said Dr. Wolinsky.

The questions that remain to be answered include: How should we mobilize patients? What is the best way to ablate the immune cells that are the target of this therapy? How should immune infections that may occur during HSCT be treated? If patients survive HSCT, how should their immune systems be reconstituted? Will HSCT trigger a reinitiation of MS? Studies of experimental therapies include the sickest patients who have the least alternatives.

Since HSCT has been disappointing in these patients, experts are questioning whether to continue studying this therapy.

"If you take patients who have progressed, and you can't stop the disease in its tracks, it's not worth doing the procedure. It would probably be better to study early-stage patients with a bad prognosis," suggested Mark S. Freedman, MD, Director, MS Research Clinic, Ottawa Hospital, Canada.

"Too many people are doing these procedures without knowing what the late effects are. We don't have enough follow-up about the late effects, and we don't know how they should be treated," stated Athanasios Fassas, MD, Director, Hematology Center and Bone Marrow Transplantation Unit, George Papanicolaou General Hospital, Thessaloniki, Greece.

Another concern is the potential for reinitiating the disease once MS patients are re-infused with their own blood cells after receiving high-dose chemotherapy. "When you reconstitute with a transfusion, patients will get the same cells back, and it is possible that they will get the disease again," said a member of the audience.

The panel debated how many patients should be studied using a treatment that has an eight percent mortality rate before the treatment is abandoned. At present, about 90 patients receiving HSCT have been studied. Medullary implants-a procedure studied in Parkinson's disease-were abandoned after disappointing results in 800 patients.

"We need to define a proper cut-off point before we do damage with a procedure," said Richard K. Burt, MD, Chief, Division of Immunotherapy and Autoimmune Disease, Northwestern University Medical School, Chicago, Illinois.

Several studies of HSCT are underway to try to resolve some of the unanswered questions. One randomized trial is comparing mitoxantrone hydrochloride (Novantrone®), a recently approved chemotherapy drug for MS, to HSCT. If this trial shows that HSCT is superior to mitoxantrone hydrochloride, then investigators would proceed with studies of HSCT.

"Hopefully, we'll need only about 200 patients to make a decision. If we see greater rates of progression and increased toxicity following HSCT, we should come to a consensus to stop studying this procedure," concluded Dr. Wolinsky.

An Oral Alpha Interferon?

The currently available disease-modifying drugs for MS are all injectable-for example, interferon beta-1a (Avonex®), interferon beta-1b (Betaseron®), and glatiramer acetate (Copaxone®). Many patients with MS have reservations about injections and would prefer to have an oral drug, which is easier to take. Oral formulations of interferon beta-1b and glatiramer acetate are in preliminary stages of development and won't be available anytime soon. A preliminary study presented at ACTRIMS suggests that an alpha interferon might prove to be a possible oral treatment for MS.

The study showed that low doses of ingested human recombinant interferon alfa-2a (hrIFN alfa-2a) reduced MS disease activity on MRI imaging by as much as 30 percent at five months compared to placebo in patients with relapsing-remitting MS (RRMS), but this effect was short-lived. The higher doses were not effective, said Stanley Brod, MD, Department of Neurology, University of Texas Health Science Center, Houston, who conducted the Phase II double-blind, placebo-controlled randomized trial in 30 subjects.

"We are still looking for the optimal dose of this ingested product before further trials can proceed," he said.

The product used in the study was injectable interferon alfa-2a (Roferon-A®), which was mixed with salt water and ground up into a drink. Study subjects drank two different amounts of the drink or a placebo look-alike drink every other day for nine months.

Dr. Brod thought that the reduced effect of the higher dose was due to the development of tolerance and, possibly, to an excessive dose. Although it is unclear why higher levels of ingested interferon alfa-2a were not as good as the lower dose, several theories are being investigated.

The ingested product was safe, with adverse events evenly distributed among the three treatment groups-placebo, low-dose interferon alfa-2a plus saline, and high-dose interferon alfa-2a plus saline. "Ingested interferon alfa-2a appears to be safe. We have exposed normal Type I diabetes patients, rheumatoid arthritis patients, and 30 MS patients to this product for a total of 15.3 patient years without clearly defined interferon-related side effects. These data support the safety concerning this route of interferon administration in human autoimmune disease."

In summary, this study suggests that ingested interferon alfa may show a systemic biological effect specific to MS and may modify asymptomatic disease activity. Additional clinical trials in relapsing remitting MS may be conducted once an optimal dose for the ingested product is identified. Further study is needed in humans to do this, said Dr. Brod.

A Formulation of Taxol® for MS?

Preliminary results of a four-year study sponsored by Angiotech Pharmaceuticals suggest that a micellar formulation of paclitaxel (Taxol®) may prove to be useful in secondary progressive MS (SPMS) and that the drug is safe and well-tolerated. Favorable trends observed in a ten-month Phase I study con- tinued during a ten- to 16-month extension phase for both clinical and MRI outcome measures. Based on these encouraging results, further clinical studies of micellar paclitaxel are being planned. A Phase II, 189-patient, double-blind, placebo-controlled, clinical study will be conducted in patients with SPMS with doses of 50 mg mІ and 75 mg mІ infused intravenously every month.

The Phase I study included 29 patients with SPMS treated with monthly IV infusions of paclitaxel at a dose of 50 mg mІ. During the extension phase, the EDSS decreased overall by 0.205 compared to baseline, with 95 percent of patients showing stabilization or improvement in EDSS over the 16 months. Encouraging trends were observed in MRI disease activity, with few adverse side effects. No serious drug-related adverse events were observed.

"These results strongly support the need for a multicenter, double-blind, placebo-controlled Phase II study of micellar paclitaxel in patients with SPMS," stated Paul O'Connor, MD, St. Michael's Hospital and the University of Toronto, Ontario, Canada.